T cells play a central role in the immune system as effectors and regulators, coupling antigen recognition and the transmission of activation signals. The diverse responses of T cells are referred to as cell-mediated immune reactions and are initiated by recognition of antigens via the T cell receptor (TCR).
T cells recognize a wide range of different antigens. As with B cells, a particular clonal line of T cells can only recognize a single antigen. However, unlike B cells, T cells recognize antigens only when they are presented to the TCR as peptides in a complex with major histocompatibility molecules (MHC) on the surface of antigen presenting cells. The TCR on most T cells consist of immunoglobulin-like integral membrane glycoproteins containing 2 polypeptide subunits, alpha and beta, of similar molecular weight. Each T-cell receptor subunit has an external amino terminal containing both a variable (V) domain and a constant (C)domain. The genes for the T-cell receptor subunits are constructed through somatic rearrangement of different gene segments, of which there are at least 3 types for the alpha; V, joining (J) and C domains, and at least types 4 for the beta; V, diversity (D), J and C domains. An invariant CD3 complex of polypeptides and a disulfide-linked homodimer are noncovalently associated with the TCR. These associated polypeptides are responsible for the signal transduction functions of the TCR and are also required for efficient surface expression of the intact receptor.
Interaction of antigen in the proper MHC context with the TCR leads to a regulated series of events resulting in differentiation, proliferation, and the acquisition of T cell immunologic function. The particular functional response depends on whether the T cell receives co-stimulatory signals through other surface receptors and which signal transduction pathways are activated (Klausner, R. D. and Samelson, L., E. (1991) Cell 64: 875-878; Clevers, H. et al. (1988) Annu. Rev. Imnmunol. 6: 629-662).
The signaling cascades initiated by TCR activation include the inositol tri-phosphate/Ca2.sup.+, diacylglycerol/protein kinase C, Ras/mitogen-activated protein kinase, and the PI 3-K pathways. Components of these pathways transmit information into the nucleus to activate the genes that code for a variety of secreted factors such as IL-2, IL-4, IL-7, IL-9, IL-10, and interferon-.gamma., which subsequently induce the proliferation, maturation, and function of cellular components of the immune system. These factors can stimulate the induction of antibody secretion and class switching in B cells, the regulation of humoral immunity, and induction of tumorocidal and anti-inflammatory activity (Alderson, M., R., et al (1991) J. Exp. Med. 173: 923-930; and Weiss, A. (1991) Annu. Rev. Genet. 25: 487-510).
The TCR antigen repertoire is established by developmentally regulated TCR gene rearrangements and is shaped by intrathymic selection processes. Immature T cells undergo a selection and differentiation process based on antigen binding prior to leaving the thymus. Those that bind self-antigens while still in the cortex of the thymus are eliminated by apoptosis, establishing immunological tolerance. Failure to eliminate self reactive populations of cells has been shown to result in autoimmune disease. Immature T cells express both CD4 and CD8 co-receptors which assist in MHC recognition; thymic maturation produces T cells expressing one or the other of these receptors. This maturation process is dependent on the structure of the surface TCR complexes expressed. Results of animal studies indicate that the successful differentiation into single-positive (bearing either CD4 or CD8) T cells requires surface expression of fully assembled TCR complexes (Shores, E. W., et al. (1993) J Immunol 150 4: 1263-1275 and Olive, C. (1995) Immunol. Cell Biol. 73: 297-307).
Defects in TCR genes, TCR expression, and T cell subtype population levels have been noted in lymphomas, leukemias, allergic responses, and autoimmune and immunodeficiency disorders. In transgenic mice deficient in the TCR alpha and beta subunits, B cells expand, differentiate and secrete copious amounts of antibodies that are reactive towards self antigens. Graft-versus-host disease is the result of normal T cell responses to cells perceived as foreign, as is the cytolitic destruction of virus infected and tumor cells. As more human TCR subunit genes are identified, additional specific functions of the TCR can be characterized (Yui, K. et al (1992) Eur J Imnmunol 22: 1693-1700; Olive, C., supra (1995); Mombaerts, P., et al (1993) Cell 75: 274-282; Wen, L., et al (1994) Nature 369 :654-658: Leiden, J., M., et al. (1986) Immunogenet. 24: 17-23: and Barber, D., F., and Lopez de Castro, J., A., Genbank accession L34734)
The discovery of a new T-cell receptor beta-like protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of cancer and autoimmune disorders.